The Janus kinases (JAK) are a family of tyrosine kinases that play a critical role in cytokine signaling. The family consists of JAK-1, JAK-2, JAK-3 and TYK-2, and the down-stream substrates of this family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses, such as allergies and asthma; autoimmune diseases, such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis; as well as in solid and hematologic malignancies, such as leukemias and lymphomas. JAK-2 has also been implicated in myeloproliferative disorders, which include polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, and systematic mast cell disease.
Therefore, there is a need to develop compounds that bind to the JAK family kinases and thereby moderate JAK/STAT signaling.